The discovery of acetylcholine receptor (AChR) antibodies in patients with myasthenia gravis (MG) led to recognition of other IgG-mediated neurologic diseases and had practical implications for serological diagnosis and immunomodulatory therapy of MG, the Lambert-Eaton myasthenic syndrome and other disorders. Our recent serological studies have implicated autoantibodies against the neuronal AChR in autonomic ganglia as the cause of acquired severe dysautonomia in some patients. In addition, these ganglionic AChR antibodies are proving to be useful serological markers of subacute autonomic neuropathy. Serum ganglionic AChR antibody levels correlate significantly with the severity of autonomic dysfunction, and a reduction in antibody level correlates with improvement in clinical and laboratory indices of autonomic function. As part of a program to nurture the career of a young neurologist clinician-investigator, we propose to develop and study animal models of autoimmunity against the ganglionic AChR to establish the etiology of human subacute autonomic neuropathy. Initial rodent experiments will examine indices of ganglionic synaptic transmission in vitro and autonomic function in vivo. Using these studies as a baseline, subsequent experiments will evaluate the effects of passive ganglionic AChR antibody transfer and active immunization on autonomic function in animals. This project is the first step toward complete understanding of a serious human neurologic disease and lays the foundation for investigating other disorders of neuronal cholinergic transmission. Novel therapeutic trials are anticipated as a clinical translational outcome of this research. The proposed project involves close interaction with established mentors at an institution with a record of excellence in clinically-relevant basic science research. The candidate has already shown potential for independent patient-based laboratory research, and with further training will develop a successful independent research program including clinically based laboratory research and translational clinical research in neurology.